The 22q11 deletion syndrome (22q11DS), also known as velocardiofacialsyndrome or DiGeorge syndrome, is the most common microdeletion syndrome in humans. Cognitive deficits occur in virtually all patients with 22q11DS, and schizophrenia or schizoaffective disorder develops in approximately 30% during their adolescence or early adulthood. Deficits in learning and memory have been identified in patients with 22q11DS and in Df(16)1/+ mice, the mouse model of this disease. However, the cellular mechanisms and gene(s) responsible for these deficits remain unknown. Recently, we discovered that long-term potentiation (LTP) of synaptic transmission, a major form of synaptic plasticity and cellular substrate of certain forms of learning and memory, is substantially altered in Df(16)1/+ mice. We determined that these changes are caused by the abnormal presynaptic function at excitatory synapses. Further experiments revealed that the increase in presynaptic function was caused by the deletion of 2 genomic regions within the large microdeletion, Df(16)2 and Df(16)5. Screening of mice with deletions of individual genes within the Df(16)2 region revealed that a deletion of the microRNA-processing gene Dgcr8 upregulates sarco(endo)plasmic reticulum ATP-ase 2 (SERCA2) in excitatory neurons and leads to abnormal neurotransmitter release and LTP. The identity of the culprit gene within the Df(16)5 region remains unknown. In this application, we propose to identify the microRNA(s) responsible for the upregulation of SERCA2 and the defects in synaptic plasticity by using electrophysiological and molecular tools, two-photon laser scanning microscopy, and two-photon uncaging. Using knockout mice recently developed in our laboratory, we will also identify the culprit gene(s) within the Df(16)5 region. Finally, we propose to test the role of the endoplasmic reticulum in presynaptic phenotypes of mouse models of 22q11DS. This information will provide a framework for the future development of therapeutic interventions to prevent or alleviate cognitive deficits in patients with 22q11DS.